Autoimmune diseases involve chronic immune responses directed at self antigens, and result in the damage or complete destruction of target tissues. Many experimental autoimmune disease, like experimental allergic encephalomyelitis (EAE), involve transient disease followed by disease resistance. We have produced mice transgenic for the rearranged genes encoding a T cell receptor (TCR) from a cloned T cell line that transfers EAE to irradiated recipients. These mice are healthy, and most of their T cells bear the transgenic encoded TCR and are activatable by myelin basic protein. However, these mice only become clinically ill if challenged with antigen in adjuvant, in which case they rapidly develop paralysis and die. When the transgene is bred to immunodeficient mice, disease develops spontaneously starting at three weeks of age. These findings suggest that regulatory lymphocytes are involved in controlling EAE, and other evidence for this also exists. We propose that autoimmune disease involves a balance between attacking and regulatory T cells, and that diversification of the attacking cells is crucial to the evolution of a chronic, debilitating autoimmune disease. Moreover, we propose that diversification occurs through the unique antigen presenting abilities of B cells. We will use our TCR transgenic mice, and mice unable to form B cells, to identify regulator T cells, to characterize their specificity and functional attributes, and to determine if diversification of the response requires specific B cells and is necessary for chronic autoimmune disease so as to assure dominance of pathogenic over regulatory T cells.